Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology.

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aß accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.

What is the radiation before 5G? A correlation study between measurements in situ and in real time and epidemiological indicators in Vallecas, Madrid.

BACKGROUND: Exposure of the general population to electromagnetic radiation emitted by mobile phone base stations is one of the greater concerns of residents affected by the proximity of these structures due to the possible relationship between radiated levels and health indicators. OBJECTIVES: This study aimed to find a possible relationship between some health indicators and electromagnetic radiation measurements. METHODS: A total of 268 surveys, own design, were completed by residents of a Madrid neighborhood surrounded by nine telephone antennas, and 105 measurements of electromagnetic radiation were taken with a spectrum analyzer and an isotropic antenna, in situ and in real - time, both outside and inside the houses. RESULTS: It was shown statistically significant p - values in headaches presence (p = 0.010), nightmares (p = 0.001), headache intensity (p < 0.001), dizziness frequency (p = 0.011), instability episodes frequency (p = 0.026), number of hours that one person sleeps per day (p < 0.001) and three of nine parameters studied from tiredness. Concerning cancer, there are 5.6% of cancer cases in the study population, a percentage 10 times higher than that of the total Spanish population. DISCUSSION: People who are exposed to higher radiation values present more severe headaches, dizziness and nightmares. Moreover, they sleep fewer hours.

Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-ß plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-ß plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

Dark microglia: A new phenotype predominantly associated with pathological states.

The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron-dense cytoplasm and nucleoplasm making them as "dark" as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3 CR1-GFP mice), and strongly express CD11b and microglia-specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses.

Microglia regulate hippocampal neurogenesis during chronic neurodegeneration.

Neurogenesis is altered in neurodegenerative disorders, partly regulated by inflammatory factors. We have investigated whether microglia, the innate immune brain cells, regulate hippocampal neurogenesis in neurodegeneration. Using the ME7 model of prion disease we applied gain- or loss-of CSF1R function, as means to stimulate or inhibit microglial proliferation, respectively, to dissect the contribution of these cells to neurogenesis. We found that increased hippocampal neurogenesis correlates with the expansion of the microglia population. The selective inhibition of microglial proliferation caused a reduction in neurogenesis and a restoration of normal neuronal differentiation, supporting a pro-neurogenic role for microglia. Using a gene screening strategy, we identified TGFß as a molecule controlling the microglial pro-neurogenic response in chronic neurodegeneration, supported by loss-of-function mechanistic experiments. By the selective targeting of microglial proliferation we have been able to uncover a pro-neurogenic role for microglia in chronic neurodegeneration, suggesting promising therapeutic targets to normalise the neurogenic niche during neurodegeneration.

Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition.

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular ß-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources.

[Urethral stricture in women]. / Estenosis uretral en la mujer.

UNLABELLED: To perform a bibliographic review on female urethra stenosis, following the criteria for evidence based medicine. METHODS: We performed a PubMed Search with the following keywords; "female urethral stricture ","women urethral stricture","female urethral reconstruction "and " female urethral stricture treatment ",without time limits, both in English and Spanish languages. RESULTS: Female urethra stenosis is a rare pathology, in which the working diagnosis is essential, as much as detailed physical examination, urodynamic study and radiological tests. We found in the literature a total of 73 cases treated with dilation with or without maintenance self catheterization, 120 cases treated with meatotomy, 65 cases treated by flap urethroplasty (46 with vaginal flap, 17 with vestibular flap and 12 with labia minora graft and 28 with oral mucosa grafts). There are not comparative studies between the various techniques, making it difficult to set up a therapeutic algorithm. CONCLUSIONS: The surgical treatment with flaps/grafts has the highest success rate; whereas less invasive procedures such as urethrotomy/meatotomy/dilations/self-catheterization should be reserved for short female urethra stenosis or women with high comorbidity.

Prognostic factors in patients with stage pT0/pT1/pTa in the radical cystectomy specimen.

OBJECTIVES: To identify risk factors for progression in patients with invasive bladder carcinoma who were pT0/pT1/pTa after cystectomy. METHODS: We analyzed the clinical records of 97 post-cystectomy pT0/pT1/pTa patients for the following variables: hydronephrosis, carcinoma in situ (CIS), lymphovascular invasion, history of non-muscular invasive disease, residual tumor in the specimen and lymphatic invasion (pN). pN+patients were excluded from definitive analysis. The quantitative and qualitative variables were analyzed using standard statistics. The chi-square test was used to analyze associations between categorical variables. Univariate Cox proportional hazard regression analysis (enter method) was performed. The Kaplan-Meier method was used to evaluate survival and the log-rank test to assess differences between groups. Statistical significance was set at p<0.05. The analysis was performed using SPSS version 15.0. RESULTS: The study sample included 97 cases. The specimen was staged at T2 in 97% of patients after transurethral resection (TUR); After cystectomy, the specimen was staged as pT0 (R0) in 44.3% and pT1/Ta (R1) in 55.7%. Median follow-up was 47 months. Lymph node metastasis were detected in 5.2% of patients (pN+rpar; and had a negative impact on survival (p=0.02). Overall survival was 59.8% and cancer-specific survival 76.6%. Univariate analysis showed a relationship between tumor progression and the presence of CIS (p < 0.001), lymphovascular invasion (p=0.049), and hydronephrosis(p < 0.001). In the multivariate analysis, only the presence of CIS in the transurethral resection was associated with reduced cancer-specific survival (HR 100.5; 95% CI, 10.8 to 933.1; pp<0.001). CONCLUSIONS: Although the prognosis of stage pT0/pT1/pTa carcinoma in the cystectomy specimen is excellent, some patients experience progression. The presence of CIS in the transurethral resection was an independent predictor of recurrence in these cases.

Cutaneous Necrosis of the Skin Secondary to Methicillin-Resistant Staphylococcus aureus (MRSA) and Bacteroides With Superimposed Herpes Simplex Virus Type II (HSV-II) in the Setting of Infective Endocarditis.

Herpes simplex virus type II (HSV-II) with superimposed bacterial skin infection is an uncommon presentation of cutaneous necrosis in the setting of infective endocarditis. This case reflects a unique presentation of an immunosuppressed patient with infective endocarditis complicated by septic emboli and cutaneous skin lesions attributable to HSV-II and superimposed bacterial skin infection. The patient presented from an outside hospital with symptoms consistent with acute onset heart failure and skin lesions. Transthoracic and transesophageal echocardiography performed there demonstrated focal thickening of the anterior mitral valve leaflet with severe mitral regurgitation. The patient then underwent extensive infectious work-up and was put on broad-spectrum antibiotics. Further work-up demonstrated greater than three DUKE minor criteria and reiterated the focal thickening of the anterior leaflet of the mitral valve, making infective endocarditis the most likely etiology. Biopsies of the skin lesions were performed which stained positive for HSV-II and grew methicillin-resistant Staphylococcus aureus and Bacteroides fragilis. The cardiothoracic surgery service ultimately decided not to perform any surgical intervention to the mitral valve during her hospitalization as she was deemed to be too high of a risk due to her thrombocytopenia and significant comorbidities. She was later discharged in hemodynamically stable condition on long-term intravenous antibiotics with repeat echocardiography demonstrating significant reduction in the mitral regurgitation and the focal thickening of the anterior leaflet of the mitral valve.

Clinical Importance of Differentiating Epstein-Barr Virus (EBV)-Positive Plasmacytoma From Plasmablastic Lymphoma: Another Unique Case of EBV-Positive Plasmacytoma in an Immunocompetent Patient.

Epstein-Barr virus (EBV)-positive plasmacytoma is a rare and unique plasma cell neoplasm that could arise in immunocompetent individuals. Given the molecular and immunohistochemical similarity of EBV-positive plasmacytomas to their significantly more aggressive counterpart, plasmablastic lymphoma (PBL), providers must distinguish between the two neoplasms. This case elucidates a presentation of EBV-positive plasmacytomas in a healthy, immunocompetent individual originating in the C4/C5 cervical neck region. The patient's clinical presentation, in combination with the surgical pathology from the mass biopsy, pointed toward EBV-positive plasmacytoma. Factors such as cellular proliferation rate, cellular atypia, and immunohistochemical staining help differentiate the two diseases. This case will further help providers in the oncologic world to identify these masses.

Does Gender Influence the Indication of Treatment and Long-Term Prognosis in Severe Aortic Stenosis?

INTRODUCTION: It is a matter of controversy whether the therapeutic strategy for severe aortic stenosis (AS) differs according to gender. METHODS: Retrospective study of patients diagnosed with severe AS (transvalvular mean gradient ≥ 40 mmHg and/or aortic valvular area < 1 cm2) between 2009 and 2019. Our aim was to assess the association of sex on AVR or medical management and outcomes in patients with severe AS. RESULTS: 452 patients were included. Women (51.1%) were older than men (80 ± 8.4 vs. 75.8 ± 9.9 years; p < 0.001). Aortic valve replacement (AVR) was performed less frequently in women (43.4% vs. 53.2%; p = 0.03), but multivariate analyses showed that sex was not an independent predictor factor for AVR. Age, Charlson index and symptoms were predictive factors (OR 0.81 [0.82-0.89], OR 0.81 [0.71-0.93], OR 22.02 [6.77-71.64]). Survival analysis revealed no significant association of sex within all-cause and cardiovascular mortalities (log-rank p = 0.63 and p = 0.07). Cox proportional hazards analyses showed AVR (HR: 0.1 [0.06-0.15]), Charlson index (HR: 1.13 [1.06-1.21]) and reduced LVEF (HR: 1.9 [1.32-2.73]) to be independent cardiovascular mortality predictors. CONCLUSIONS: Gender is not associated with AVR or long-term prognosis. Cardiovascular mortality was associated with older age, more comorbidity and worse LVEF.

Autophagy in periodontitis patients and gingival fibroblasts: unraveling the link between chronic diseases and inflammation.

BACKGROUND: Periodontitis, the most prevalent chronic inflammatory disease, has been related to cardiovascular diseases. Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. The aim of this research was to study the role of autophagy in peripheral blood mononuclear cells from patients with periodontitis and gingival fibroblasts treated with a lipopolysaccharide of Porphyromonas gingivalis. Autophagy-dependent mechanisms have been proposed in the pathogenesis of inflammatory disorders and in other diseases related to periodontitis, such as cardiovascular disease and diabetes. Thus it is important to study the role of autophagy in the pathophysiology of periodontitis. METHODS: Peripheral blood mononuclear cells from patients with periodontitis (n = 38) and without periodontitis (n = 20) were used to study autophagy. To investigate the mechanism of autophagy, we evaluated the influence of a lipopolysaccharide from P. gingivalis in human gingival fibroblasts, and autophagy was monitored morphologically and biochemically. Autophagosomes were observed by immunofluorescence and electron microscopy. RESULTS: We found increased levels of autophagy gene expression and high levels of mitochondrial reactive oxygen species production in peripheral blood mononuclear cells from patients with periodontitis compared with controls. A significantly positive correlation between both was observed. In human gingival fibroblasts treated with lipopolysaccharide from P. gingivalis, there was an increase of protein and transcript of autophagy-related protein 12 (ATG12) and microtubule-associated protein 1 light chain 3 alpha LC3. A reduction of mitochondrial reactive oxygen species induced a decrease in autophagy whereas inhibition of autophagy in infected cells increased apoptosis, showing the protective role of autophagy. CONCLUSION: Results from the present study suggest that autophagy is an important and shared mechanism in other conditions related to inflammation or alterations of the immune system, such as periodontitis.

Urachal adenocarcinoma. Case report and bibliographic review.

OBJECTIVE: Literature review of adenocarcinoma of the urachus in connection with two cases recently diagnosed and treated in our center. METHODS/RESULTS: We report 2 cases of urachus Adenocarcinoma treated in our institution, both underwent extended partial cystectomy including excision of the urachus up to the umbilicus. CONCLUSION: Urachal adenocarcinoma is an exceptional tumor, of poor prognosis, the treatment of which is surgical (partial cystectomy), and the main predictors of disease-free survival are the degree of tumor differentiation and the free margins of the surgical specimen.

[Rescue cryotherapy for prostate cancer after radiotherapy]. / Crioterapia de rescate en el cáncer de próstata después de radioterapia.

Radical Radiotherapy constitutes a useful therapeutic option for localized prostate cancer. Almost one third of prostate cancer patients choose this alternative to treat the disease. Despite modifications in the technique as intensity modulation, 3D conformational radiotherapy or computer-assisted brachytherapy, a significant percentage of these patients will show an increase in PSA values after radiation. Local relapse without distant disease and PSA less than 10 ng/ml are candidates for salvage therapy. Cryotherapy has already become a curative treatment option in this group of patients. Recent technological as well as surgical advances in salvage-cryotherapy have reduced dramatically complications and progressively increase the interest on this alternative.

Primary renal Ewing's sarcoma.

OBJECTIVE: To report two new cases of Ewing's sarcoma/primitive neuroectodermal tumor of the kidney, one of them with tumor thrombus in cava. METHOD: Characterization of two new cases and literature review by PubMed search. RESULTS: We report the cases of two men diagnosed with primary renal Ewing's sarcoma, who have been treated with nephrectomy and adjuvant chemotherapy, being in complete remission to date. CONCLUSION: Ewing's sarcoma / primitive neuroectodermal tumor of the kidney is a rare condition that mainly affects young adults. The natural history of these tumors is the evolution towards metastatic disease and death. Treatment is multimodal, combining surgery and chemotherapy. The role of radiotherapy is not well established.

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aß pathology.

The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased ßgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aß, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aß pathology in AD.

Villous adenoma in augmentation colocystoplasty asociated to infiltrating urotelial cancer in bladder remanent.

OBJECTIVE: To report a new case of villous adenoma developed in augmentation colocystoplasty. METHODS: Characterization of a new case and review of the literature published to date. RESULTS: We report the case of a 66 year-old man with a villous adenoma and synchronic infiltrating transitional cell carcinoma of the bladder after augmentation colocystoplasty. The latency period until the development of villous adenoma after surgery is long. Treatment consisted of transurethral resection. CONCLUSIONS: Villous adenoma is a benign neoplasm that occurs in the colonic mucosa and shows a high ability to become a malignant colonic cancer. Only two cases of villous adenoma in augmentation colocystoplasty have been reported. We recommend follow up with periodic cystoscopy because of its high malignancy potency.

Novel presenilin 1 mutation (p.Thr-Pro116-117Ser-Thr) in a Spanish family with early-onset Alzheimer's disease.

Presenilin 1 (PSEN1) is a γ-secretase component, which is in charge of the amyloid precursor protein (APP) cleavage. APP is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). PSEN1 mutations are the most important causes of familial AD, being related to the earlier onset and rapid progression of the disease. Presenilins and APP mutations represent an extraordinary opportunity to study the pathophysiology of AD. We describe the clinical and genetic study of a 37-year-old male patient with a novel mutation in PSEN1 (p.Thr-Pro116-117Ser-Thr). We have studied the pedigree of his family with a further 9 members affected, all of them with onset in their 30s. We have also described the clinical data and results of brain biopsies in 2 of them. DNA sequencing of a tissue sample from an uncle of the patient, who died of AD in the 80s, showed the same mutation as in the patient. These data and predictive analysis indicate the pathogenicity of the mutation.